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Transportin-1: a Nuclear Import Receptor with Moonlighting Functions Allegra Mboukou, Vinod Rajendra, Renata Kleinova, Carine Tisné, Michael Jantsch, Pierre Barraud

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Transportin-1: a Nuclear Import Receptor with Moonlighting Functions Allegra Mboukou, Vinod Rajendra, Renata Kleinova, Carine Tisné, Michael Jantsch, Pierre Barraud Transportin-1: A Nuclear Import Receptor with Moonlighting Functions Allegra Mboukou, Vinod Rajendra, Renata Kleinova, Carine Tisné, Michael Jantsch, Pierre Barraud To cite this version: Allegra Mboukou, Vinod Rajendra, Renata Kleinova, Carine Tisné, Michael Jantsch, et al.. Transportin-1: A Nuclear Import Receptor with Moonlighting Functions. Frontiers in Molecular Biosciences, Frontiers Media, 2021, 8, pp.638149. 10.3389/fmolb.2021.638149. hal-03171125 HAL Id: hal-03171125 https://hal.archives-ouvertes.fr/hal-03171125 Submitted on 16 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. REVIEW published: 18 February 2021 doi: 10.3389/fmolb.2021.638149 Transportin-1: A Nuclear Import Receptor with Moonlighting Functions Allegra Mboukou 1, Vinod Rajendra 2, Renata Kleinova 2, Carine Tisné 1, Michael F. Jantsch 2 and Pierre Barraud 1* 1Expression Génétique Microbienne, Institut de Biologie Physico-Chimique (IBPC), UMR 8261, CNRS, Université de Paris, Paris, France, 2Department of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria Transportin-1 (Trn1), also known as karyopherin-β2 (Kapβ2), is probably the best- characterized nuclear import receptor of the karyopherin-β family after Importin-β, but certain aspects of its functions in cells are still puzzling or are just recently emerging. Since the initial identification of Trn1 as the nuclear import receptor of hnRNP A1 ∼25 years ago, several molecular and structural studies have unveiled and refined our understanding of Trn1-mediated nuclear import. In particular, the understanding at a molecular level of the NLS recognition by Trn1 made a decisive step forward with the identification of a new class of NLSs called PY-NLSs, which constitute the best-characterized substrates of Trn1. Besides PY-NLSs, many Trn1 cargoes harbour NLSs that do not resemble the archetypical PY-NLS, which complicates the global understanding of cargo recognition by Trn1. Although PY-NLS recognition is well established and supported by several Edited by: structures, the recognition of non-PY-NLSs by Trn1 is far less understood, but recent Maria Rosaria Conte, King’s College London, reports have started to shed light on the recognition of this type of NLSs. Aside from its United Kingdom principal and long-established activity as a nuclear import receptor, Trn1 was shown more Reviewed by: recently to moonlight outside nuclear import. Trn1 has for instance been caught in Tobias Madl, Medical University of Graz, Austria participating in virus uncoating, ciliary transport and in modulating the phase Roberta Spadaccini, separation properties of aggregation-prone proteins. Here, we focus on the structural University of Sannio, Italy and functional aspects of Trn1-mediated nuclear import, as well as on the moonlighting *Correspondence: activities of Trn1. Pierre Barraud [email protected] Keywords: karyopherin, karyopherin-β2, nucleo-cytoplasmic transport, NLS, proline–tyrosine nuclear localization signal, phase-separation, FUS, TNPO1 Specialty section: This article was submitted to Structural Biology, 1 INTRODUCTION a section of the journal Frontiers in Molecular Biosciences In eukaryotic cells, the presence of a physical separation between the nucleus and the cytoplasm in Received: 05 December 2020 the form of a double membrane assures a physical and temporal separation of the transcription and Accepted: 13 January 2021 translation processes but creates the need for a selective and efficient transport of thousands of Published: 18 February 2021 macromolecules across the nuclear envelope (Görlich and Kutay, 1999; Conti and Izaurralde, 2001; Citation: Fried and Kutay, 2003; Cook et al., 2007). This continual ballet, with controlled bidirectional flows, is Mboukou A, Rajendra V, Kleinova R, orchestrated by nuclear transport receptors (NTRs) that carry their cargoes from one compartment Tisné C, Jantsch MF and Barraud P (2021) Transportin-1: A Nuclear Import to the other by crossing the nuclear envelope at the level of the nuclear pore complexes (NPCs) (Tran Receptor with Moonlighting Functions. and Wente, 2006; Wente and Rout, 2010; Allegretti et al., 2020). Transport receptors of the Front. Mol. Biosci. 8:638149. karyopherin-β (Kapβ) family account for the vast majority of the cargo flow through the NPC. doi: 10.3389/fmolb.2021.638149 Karyopherins interact selectively with proteins of the NPC, namely the phenylalanine-glycine Frontiers in Molecular Biosciences | www.frontiersin.org1 February 2021 | Volume 8 | Article 638149 Mboukou et al. Trn1: Nuclear Import and Moonlighting nucleoporins (FG-Nups), which surround and line the NPC transport receptors. Trn1 was in fact later shown to only central channel (Hampoelz et al., 2019). Within the NPC, function in nuclear import, with the hnRNP A1 cargo being these FG-Nups built and establish the proper operation of the released from Trn1 upon RanGTP binding (Siomi et al., 1997; permeability barrier (Fu et al., 2018). In general, large Izaurralde et al., 1997), a common trait of nuclear import macromolecules (>40 kDa) are indeed excluded from the NPC receptors, but the terminology has remained. channel, whereas karyopherins can cross the NPC barrier on In the Kapβ family, Trn1 shares the highest sequence identity account of their common property to selectively interact with FG- (83%) with Transportin-2 (Trn2), also known as karyopherin- Nups (Rout et al., 2003; Weis, 2007; Hülsmann et al., 2012; Beck β2B (Kapβ2B) (Twyffels et al., 2014). Trn2 exists in two isoforms and Hurt, 2017). called Trn2A or Kapβ2B(A) (Siomi et al., 1997) and Trn2B or Karyopherins that mediate nuclear import are also known as Kapβ2B(B) (Shamsher et al., 2002), the expression of which importins, whereas those mediating nuclear export are known as results from an alternative splicing event (Rebane et al., 2004). exportins. Besides the binding to FG-Nups, importins and This high sequence similarity between Trn1 and Trn2 correlates exportins associate with their cargoes via signals, namely with a highly similar cargo spectrum for these two NTRs. Among nuclear localization signals (NLSs) and nuclear export signals different karyopherins, Trn1 indeed presents the highest degree (NESs), which determine whether the cargo is imported in or of functional redundancy with Trn2 in terms of cargoe specificity exported out of the nucleus (Chook and Süel, 2011; Xu et al., (Mackmull et al., 2017; Kimura et al., 2017). Their cargoes include 2010; Cook and Conti, 2010). Importins bind to their cargoes in many RNA-binding proteins involved in mRNA processing, such the cytoplasm, reach the NPCs and translocate to the other side of as proteins of the hnRNP family (e.g., hnRNP A1, hnRNP A2/B1, the nuclear envelope, where they release their cargoes upon hnRNP D, hnRNP F, hnRNP H, hnRNP M), but also other binding to the small GTPase Ran in its GTP-bound form protein families implicated in nucleic-acid-related functions in (RanGTP). In a reciprocal manner, exportins associated with the nucleus. Although the exclusive import of specific cargoes by RanGTP bind to their cargoes in the nucleus, reach the NPCs and either Trn1 or Trn2 have not been experimentally confirmed, a translocate to the other side of the nuclear envelope, where they high-throughput study suggested a slight specialization of these dissociate from their cargoes upon GTP hydrolysis and RanGDP NTRs. Cargoes with efficient NLSs would be imported by any of release (Conti and Izaurralde, 2001; Fried and Kutay, 2003; Weis, the two Transportins, whereas cargoes with less efficient NLSs 2003). Transport directionality is thus primarily driven by the might be exclusively carried by either Trn1 or Trn2 (Kimura et al., RanGTPase nucleotide cycle, which produces an asymmetric 2017). For instance, actin and actin-related proteins implicated in distribution of RanGTP and RanGDP on both sides of the chromatin remodeling and transcription, and proteins related to nuclear envelope, with RanGTP being present at high nuclear division, would preferentially be imported by Trn1, concentrations in the nucleus and with RanGDP being mainly whereas proteins related to DNA repair would preferentially present in the cytoplasm (Izaurralde et al., 1997; Dasso, 2002). be Trn2 cargoes (Kimura et al., 2017). These recent studies Transport selectivity, on the other hand, relies on the selective aiming at defining the cargo spectrum of individual NTRs binding of NTRs to their cargoes via the selective recognition of clearly provide insightful information on NTR-cargo their signals. recognition. However, these studies must be analyzed with Within the Kapβ family, Transportin-1 (Trn1), also known as caution, since among the few hundreds of potential Trn1 karyopherin-β2 (Kapβ2), is probably the best-characterized cargoes identified in two recent reports, only ∼20 are common nuclear import receptor after Importin-β [also known as to the two datasets (Mackmull et al., 2017; Kimura et al., 2017; karyopherin-β1 (Kapβ1)]. Despite nearly identical
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